Research
Glossary
Allele: A known variation (version) of a particular gene.
APEX (arrayed primer extension): A type of genotyping method that allows multiple genotypes to be generated in one experiment. The method utilizes several oligonucleotide probes that are specific for a particular SNP and match the sequence just before the polymorphic site. The end of each oligonucleotide is modified to allow its covalent attachment to a glass slide. Each SNP is amplified by PCR and the DNA added to the bound oligonucleotides on the glass slide. An extension reaction is carried out using a thermostable DNA polymerase. Four unique, fluorescently-labelled nucleotides are used to extend each probe by only one base, dependent on the individual's template DNA. Following removal of all unincorporated dye as well as the template DNA, the SNPs are detected by the wavelength of fluorescence from the dyes at each site on the array.
Coriell: The Coriell Cell Repositories provide research reagents to the scientific community by establishing, maintaining and distributing cell cultures and DNA derived from the cell cultures.
DNA (deoxyribonucleic acid): The large double-stranded molecule carrying the genetic code. It consists of four bases (adenine, guanine, cytosine and thymine), phosphate and ribose.
Gene: The term coined by Johannsen (1909) for the fundamental physical and functional unit of heredity. The word gene was derived from De Vries' term pangen, itself a derivative of the word pangenesis which Darwin (1868) had coined. A gene is an ordered sequence of nucleotides located in a particular position (locus) on a chromosome that encodes a specific functional product (the gene product, i.e. a protein or RNA molecule). It includes regions involved in regulation of expression and regions that code for a specific functional product.
Gene expression: The process by which a gene's coded information is converted into the structures present and operating in the cell. Expressed genes include those that are transcribed into mRNA and then translated into protein and those that are transcribed into RNA but not translated into protein (e.g. transfer and ribosomal RNAs).
Genome: The entire complement of genetic material in an organism.
Genomic control: An experimental approach to determine if a population is from a single ethnic group or is a mixture of ethnic groups. Neutral polymorphisms randomly selected from the genome are typed in the patients and controls. The polymorphisms are neutral in the sense that they have no effect on gene function and are therefore unlikely to be associated with disease. If there is a difference in the frequency of these neutral polymorphisms between the patients and controls, this indicates that the individuals in these two groups are not from the same ethnic background. We determine if an allele is a susceptibility factor for disease by looking for differences in the frequency of that allele between cases and controls. If neutral polymorphisms differ in frequency between cases and controls then nothing can be inferred if a putative disease-causing allele differs in frequency also. Therefore, use of genomic controls protects against spurious (false positive) associations.
Genotype: A somewhat poorly defined term. Most often it refers to the set of alleles at a single point on a chromosome. Confusingly, it is also used to mean an organism's entire genetic makeup (thus overlapping with the term "genome").
Haplotype: The alleles of a set of closely linked genetic markers present on one chromosome which tend to be inherited together.
Haplotype tag SNP: A SNP that can be used to identify, i.e. tag, a haplotype in a given region of the genome. The information from a haplotype tag SNP (htSNP) can be used to infer the presence of all the alleles that form the haplotype.
Heterozygote: an individual who has inherited two different alleles at a particular locus.
Homozygote: an individual who has inherited two identical copies of an allele at a particular locus.
International HapMap Project: is an organization whose goal is to develop a haplotype map of the human genome (the HapMap), which will describe the common patterns of human genetic variation. The HapMap is a key resource for researchers to use to find genes affecting health, disease and responses to drugs and environmental factors. The information produced by the project has been made freely available to researchers around the world, and there are now 2 phases available. The website is http://www.hapmap.org.
Intermediate phenotype: a phenotype used in the search for disease-causing genes that represents one of the steps in the pathway to the disease but is not the clinical condition itself e.g. lipid levels in atherosclerosis or blood coagulation factor levels in sepsis. These phenotypes are intermediate between the genetic polymorphism under study and the eventual disease outcome.
Linkage disequilibrium: Linkage disequilibrium (often termed "allelic association") is a situation when alleles at two separate loci occur together on chromosomes more frequently than expected by chance alone. Linkage disequilibrium tends to only occur between loci that are very close to each other on a chromosome.
Locus: The position of a gene or a genetic marker on a chromosome. Plural: loci.
Microarray spotter: A high-precision robot with metal pins that dip into a DNA solution, suck up a specific volume and deposit the DNA onto a glass slide in a pre-arranged pattern.
Normalised DNA: A group of DNA samples that has been adjusted so that each sample is at the same concentration, thus making subsequent genotyping easier and more accurate.
Nucleotides: The building blocks of nucleic acids such as DNA.
Oligonucleotides: Short sequences of nucleotides (often simply referred to as oligos).
PCR (polymerase chain reaction): Amplification of specific lengths of DNA by repeated 'thermal cycling' reactions using an enzyme such as Taq DNA polymerase.
Phenotype: The term coined by Johannsen (1909) for the appearance (Gk. phainein, to appear) of an organism with respect to a particular character or group of characters (physical, biochemical, and physiologic), as a result of the interaction of its genotype and its environment. We most often use the different diseases that we study as the phenotype of interest.
Polymorphism: Difference in DNA sequence among individuals. Usually the term only applies to genetic variations occurring at a frequency of more than 1%.
SeattleSNPs: Also known as the UW - FHCRC Variation Discovery Resource. SeattleSNPs is a collaboration between the University of Washington and the Fred Hutchinson Cancer Research Center, funded as part of the National Heart Lung and Blood Institute's (NHLBI) Programs for Genomic Applications (PGA). The goal of SeattleSNPs is to discover and model the associations between single nucleotide sequence differences in the genes and pathways that underlie inflammatory responses in humans. They identify the common variable sites and establish their relative frequencies and haplotypes in two human populations having different evolutionary histories. We use this information, available at the Seattle SNPs website (http://pga.gs.washington.edu/), for identifying which polymorphisms we will investigate.
SNP (single nucleotide polymorphism): A DNA sequence variation that involves a change in a single nucleotide (SNP is often pronounced "snip").
Taq DNA polymerase: A thermostable DNA polymerase, originally isolated from Thermus aquaticus, an organism that resides in hot springs. This is the enzyme that makes copies of a DNA molecule in PCR reactions.
TaqMan: TaqMan is a type of assay patented by Roche Molecular Systems. We use this assay for genotyping the samples in our cohorts. In general, TaqMan assays utilize an oligonucleotide probe that is specific for the target gene. This probe is labelled with a fluorescent tag and a quenching molecule. During the extension step of a PCR the Taq enzyme will disrupt probe bound to the target separating the fluorescent tag from its quencher molecule thus permitting fluorescence. For genotyping assays, we use two probes rather than one. Each probe is specific for a given allele of a polymorphism. The two probes can be distinguished because they are labelled with different tags that fluoresce at different wavelengths.
TDT: The Transmission Disequilibrium Test is a type of analysis to determine whether an allele or haplotype is a risk factor for a disease. The approach assumes that a parent heterozygous for a marker linked to a disease locus will transmit the associated allele to an affected child more often that not i.e. >50% of the time. The TDT is immune to the problems of false positive results due to the use of an ethnically mixed population that may be encountered in association studies of unrelated individuals.